Project Summary Host-microbial interactions are a critical determinant of health. In the gastrointestinal tract, there are several overlapping mechanisms of host defense that function together to prevent entry of pathogens into the body. These protective mechanisms are provided through the coordinated efforts of intestinal epithelial cells and immune cells in the lamina propria. Although sensory neurons and neurotransmitters are known to exacerbate intestinal inflammation, it has only recently been established that sensory neurons can suppress host response to pathogenic bacteria in the skin and lung. Unlike these other sites, our preliminary data indicates that sensory neurons are key to host- protective immunity to enteric bacterial pathogens. The overall goals of this project are to determine precisely define the role of the neuro-immune communication in response to enteric bacterial pathogens such as Citrobacter rodentium. This will be achieved by selective ablation of sensory neurons, and use of knockout mice with targeted deficiency in the polymodal nociceptive receptor TRPV1 (SA1.1). To determine if enteric pathogens can directly activate these neurons, an in vitro approach will be used with primary cultures of sensory neurons (SA1.2). The role of the predominant sensory neurotransmitter, Substance P (Tac1), during enteric infection will be assessed using bone marrow chimera approach with WT or Tac1 KO mice as donors and recipients (SA2.1). As Substance P is a potent chemoattractant that can induce chemokine and adhesion molecule expression, the role of this molecule in mediating T- cell recruitment will be assessed (SA2.2). Together, these proposed studies will decipher the contribution of the sensory nervous system and a unique immune cell population to mucosal host defense.